Abbreviations
AMPK: AMP-dependent kinase; BBB: Blood-brain-barrier; BPC: Best
physician’s choice chemotherapy; CCF: Cytokinetic cleavage furrow; DSBs:
DNA double-strand breaks; DSC-PWI: Dynamic susceptibility
contrast-perfusion weighted imaging; DTI: Diffusion tensor imaging; ECM:
Extracellular matrix; EF: Electric field; EMT: Epithelial-mesenchymal
transition; FDA: The US Food and Drug Administration;18F-FDG:18F-2-fluoro-2-deoxy-D-glucose; FET:
O-(2-18F-fluoroethyl)-L-tyrosine; AMT:
Alpha[11C]-methyl-L-tryptophan;18F-DASA-23:
1-((2-fluoro-6-18F-fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine;
PKM2: Pyruvate kinase M2; GBM: Glioblastoma; HIF1α: Hypoxia-inducible
factor 1α; HMGB1: High-mobility group box 1; MA: Mesenchymal
astrocytoma; MMP: matrix metalloproteinase; MPS1: Monopolar spindle 1;
MRI: Magnetic resonance imaging; ndGBM: Newly diagnosed glioblastoma;
NF-κB: Nuclear factor kappa-B; NSCLC: Non-small cells lung cancer; OS:
Overall survival; PD-1: Programmed cell death protein 1; PET: Positron
emission tomography; PFS: Progression-free survival; PKM2: Pyruvate
kinase M2; rGBM: Recurrent glioblastoma; RT: Radiation treatment; SOC:
Standard of care; SRS: Stereotactic radiosurgery; TMZ: Temozolomide;
T1IFNs: Type 1 interferons; TTFields: Tumor treating fields; VEGF:
Vascular endothelial growth factor.
INTRODUCTION
Malignant brain tumors are the most devastating disease in the central
nervous system which seriously threatening human health. Among them,
glioblastoma multiforme (GBM) is the most common and deadliest primary
neoplasm with high mortality and inevitable recurrence[1]. Despite
the extensive development of multidisciplinary treatment approaches
involving extensive surgery, chemotherapy and radiotherapy, the
prognosis of GBM remains discouraging. Conventional approaches provide
limited effectiveness for malignant brain tumors due to late diagnosis,
unspecific location, and tumor heterogeneity, leading to unbearable
adverse effects[2, 3]. T{Rivoirard, #345}argeted therapy and
immunotherapy (e.g., gefitinib and trastuzumab) have shown modest
efficacy, because of the poor permeability of blood-brain-barrier
(BBB)[4-6]. Therefore, it’s urgent to develop a more effective and
safer therapy.
TTFields are a novel tumor therapy which inhibit the proliferation and
growth of tumor by delivering alternating electrical field (EF) at low
intensity (1-3 V/cm) and intermediate frequency (100-300
kHz)[7]. As a physical local
therapy, TTFields do not cause serious systemic side effects and without
therapeutic resistance[8, 9]. With the excellent clinical outcomes
had been reported, TTFields have already been approved by the US Food
and Drug Administration (FDA) for the treatment of patients with newly
diagnosed glioblastoma (ndGBM), recurrent glioblastoma (rGBM), and
malignant pleural mesothelioma[8-10].
Afterwards, breakthroughs have been made in the in vitro or animal
studies on the biological mechanisms of TTFields.
Alone with the preclinical research,
clinicians have carried out some significant trials of TTFields,
including the combined treatments or triple treatment, making
TTFields a promising candidate in
combination with other therapies. In this article, we will review the
anti-tumor mechanism of TTFields and discuss the emerging framework of
TTFields-based combination therapy for malignant brain tumors.
ANTI-TUMOR MECHANISMS OF TTFIELDS
Tissues and cells possess endogenous EF that influence biological
activities and cellular events. The biological circuitry of cancer cells
is modified, and manipulating their bioelectrical properties may lead to
new modalities for cancer treatment[11]. Exogenous EF has been long
exploited for interference and/or stimulation of certain natural
biological processes, such as depolarization of nerves, contraction of
muscles, embryonic development and heat production of tissues[12].
Intermediate-frequency alternating EF had been neglected by the capacity
of neither generating heat nor triggering action potentials[13].
Emerging studies have reported that TTFields can alter the bioelectrical
state of macromolecules and organelles involved in cancer biology, thus
showcasing the therapeutic potential to against tumors in multiple ways.
Moreover, the whole proteomic and transcriptomic analyses proved the
massive alteration of differentially expressed proteins, mRNAs, miRtNAs,
lncRNAs, and circRNAs by TTFields in GBM cells which are related to cell
mitosis-related events, varied cellular biological processes, and
multiple organelle structures and activities[14].
TTFields interfere with cancer cell mitosis
The inhibition of cell mitosis is the most common reported mechanism of
TTFields, and TTFields targets cancer cells through the unusual
electrical polarity and rapid proliferative properties. Considering that
all charged particles and dipoles in cell will respond to EF/currents
and will oscillate as EF forces alternate in opposite
directions[15], and dividing cells contain highly polar, spatially
oriented microtubules and septins, TTFields are capable of interfering
with cell mitosis and leading to arrest of proliferation[7].
Specifically, during normal metaphase, tubulins are precisely
choreographed and arranged to form microtubule spindles that extend into
the genetic material lining the center of the cell and bind to
chromosomes[16, 17]. When exposed to TTFields, tubulin is forced to
align along the direction of EF, resulting in the interference of
tubulin polymerization and obstruction of microtubule spindle formation
(Figure 1A)[7]. Another important basis of the effect of TTFields in
dividing cells is the directional, hourglass-shaped cell morphology
during the cytokinesis phase[7]. At the late stage of cell mitosis,
the mitotic septin complex composes of septin 2, 6, and 7, which will be
repositioned in alternating EF, leading to aberrant localization of the
cytokinetic cleavage furrow (CCF), which results in improper cell
division[18]. Septins cross-link to F-actin bundles within the
submembrane actin cytoskeleton and must be sufficiently stiff to
withstand the hydrostatic pressure generated within the cytoplasm by the
invasion of CCF[19, 20].{Gilden, 2012 #415;Tooley, 2009
#416;Tooley, 2009 #416} In cytokinesis, the applied EF intensity in
dividing cell shows an hourglass-like non-uniform field distribution,
and all polar macromolecules and organelles will be pushed towards the
CCF where the EF intensity is highest (Figure 1B)[21-23]. This
so-called mesoelectrophoresis prevents cells from dividing properly.
Catastrophic mitotic errors occur in late mitosis are impossibly
rectified, and the cell membrane will rupture and
blister[24].
TTFields disrupt genomic integrity
During intherphase, TTFields possess the function of disrupting the
integrity of genome, leading to efficient cytocidal actions against
tumor cells. The phosphorylation level of γ-H2AX, an indicator of DNA
damage, was higher when combining TTFields with radiation treatment (RT)
than RT alone[25]. RT-induced cytotoxicity depends on the extent of
DNA double-strand breaks (DSBs) repair, most of which are repaired
within 24 hours after RT. In TTFields-treated cells after RT, more than
40% of DSB failed to be repaired, indicating the efficacy of TTFields
to enhance RT-damaged DNA may through blocking the homologous
recombination repair pathway[26]. The expression of BRCA1 pathway
genes was found significantly down-regulated during TTFields
treatment[27]. BRCA1 pathway not only plays a vital role in
homologous recombinant DNA repair[28], but maintains the stability
of DNA replication forks in association with the Fanconi anemia proteins
and promotes alternative end-joining DNA repair[29]. Therefore, DNA
replication stress increased by TTFields, including the reduction of
replication fork speed and the increase in R-loop formation, resulting
in the disruption of DNA integrity[30]. In turn, TTFields not only
slow DNA damage repair kinetics but induce replication stress in cancer
cells, and the end is cell death (Figure 1C).
TTFields inhibit cell migration and invasion
TTFields have been reported with the capacity to inhibit the metastatic
spread of solid tumors[31]. Tumor metastasis is a multi-step
process, including tumor cell invasion of basement membranes and
movement to surrounding tissues, intravasation into blood vessels, and
spreading to other organ sites. It’s well known that microtubules in
TTFields-treated cells tend to align with the EF. Alterations of
microtubules lead to the mediation of the GEF-H1/RhoA/ROCK signaling
pathway and the consequent formation of focal adhesions and induction of
peripheral actin bundling, thereby hindering the motility of cancer
cells (Figure 1D)[18]. TTField also exert the suppression of
ciliogenesis in GBM cell lines which related with the development of
tumor and the resistance to therapy[32].
Epithelial-mesenchymal transition (EMT) programs contribute to the
acquisition of aggressive properties by enhancing the motility of cancer
cells, damaging the intercellular junctions, and remodeling the
extracellular matrix (ECM)[33]. EMT-related biomarkers in GBM cells
were found significantly affected by TTFields involving a series of
potential mechanisms. Remarkably, mesenchymal markers (e.g., vimentin,
smooth muscle actin) were down-regulated, while epithelial markers
(e.g., the adherens junction protein E-cadherin) was up-regulated, and
its loss serves as the core role in the loss of epithelial
differentiation[34]. ECM is the first tissue barrier to prevent
tumor invasion peripherally which can be degraded by matrix
metalloproteinases (MMPs). TTFields can inhibit the degradation of ECM
by suppressing the expression of nuclear factor kappa-B (NF-κB), a
transcription factor that regulates the expression of MMPs[34, 35].
Besides, the migration and invasion of cancers require an adequate
supply of oxygen and nutrients, hence neovascularization is a decisive
factor in cancer progression[36]. The levels of hypoxia-inducible
factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) were
decreased in TTFields-treated cells, leading to reduced
angiogenesis[34]. Furthermore, a significant time-dependent
inhibition in PI3K/AKT and MAPK signaling was observed in the
TTFields-treated cells, resulting in a reduction in cell migration and
invasion by decreasing EMT- and ECM- related marker expression and
reducing angiogenesis (Figure 1D)[34].
TTFields intervene autophagy process
Abnormal mitotic events can invite autophagy to occur (Figure
1E)[37]. When exposed to TTFields, the expression of autophagosome
marker LC-Ⅱ/LC-I was increased and the cells exhibited typical signs of
autophagy[38]. Akt2/mTOR/p70S6K axis (a negative regulator of
autophagy) is a vital regulator of autophagy by TTFields. Moreover, many
miRNAs can be induced by TTFields, especially miR-29b which directly
target Akt2 to trigger autophagy[39]. In most cases, autophagy can
maintain the organization and stability of the centrosome to protect
cells[40], while in the presence of the autophagy inhibitor
3-methyladenine, the number of dead GBM cells treated with TTFields was
diminished, indicating that autophagy mediated TTFields-induced cell
death[38]. Such called “autophagic programmed death” may be an
alternative to programmed cell death[41].
However, inconsistent findings have been reported. Some studies proposed
that autophagic flux might be interrupted by TTFields[14]. Autophagy
may be a protective mechanism of cells against TTFields in some cases.
Phosphorylated AMP-dependent kinase (AMPK) can inhibit mTORC1, thereby
suppressing its ability to negatively regulate autophagy. Depletion of
AMPK inhibits the up-regulation of autophagy in response to TTFields and
sensitized GBM cells to treatment[42]. It is unknown whether
autophagy exerts a protective or killing effect on TTFields-treated
cancer cells and may be relevant to the genetic traits of cancer cells,
remains to be further investigated.
TTFields induce anti-tumor immune response
Systemic anti-tumor immune responses
can be activated in TTFields-treated tumor-bearing animals (Figure
1F)[31]. High doses of dexamethasone could interfere with the
therapeutic effect of TTFields on rGBM[43]. In TTFields-treated
cells, damage-related molecular patterns including high-mobility group
box 1 (HMGB1) and ATP were released, and calreticulin was exposed on the
cell surface leading to increased infiltration of antigen-presenting
cells into the tumor. Endoplasmic reticulum stress induced by TTFields
may be the trigger that drives exposure of calreticulin to the cell
surface[44]. The dying cells release ATP, which serves as a “find
me” signal of apoptotic cells to increase the recruitment of
lymphocytes to induce immunogenic cell death of cells[45].
Furthermore, cell death caused by TTFields can promote the maturation
and phagocytosis of dendritic cells[44].
Emerging evidence suggested that TTFields fostered the activation of RAW
264.7 macrophages and its output of NO and ROS. When co-cultured with
4TI cells under TTFields, macrophages secreted elevated levels of
pro-inflammatory cytokines, like IL-1β, TNF-α, and IL-6, and the
viability of 4TI cells were diminished. Besides, the phosphorylation
levels of IκB-α, NF-κB p65 subunit, and p38 MAPK were observed higher in
TTFields-treated RAW 264.7 cells than control, indicating that TTFields
induced the p38 MAPK/NF-κB pathway of macrophages to exert inflammatory
effects[46].
Recently, TTFields were reported to
cause local disruption of the nuclear envelope of cancer cells during
interphase, resulting in the release of large cytoplasmic clusters of
naked micronuclei, which recruited and activated two major DNA sensors
(cGAS and AIM2). Subsequently, the activated cGAS/STING inflammasome
tended to up-regulate pro-inflammatory cytokines, type 1 interferons
(T1IFNs) and T1IFN-responsive genes, thereby activating the peripheral
immune system and creating a potential intrinsic immune platform for
cancers[47] (Figure 1C).
TTFields increase cell membrane permeability
When applying high pulsed EF to the cells, depending on the field
intensity, irreversible electroporation, induction of necrotic cell
death, or reversible electroporation may occur[48]. In
TTFields-treated glioblastoma cells, the number and size of membrane
pores were reversibly increased, allowing greater permeability to
substances as large as 20 kDa (e.g., 5-aminolevulinic acid) but not
exceeding 50 kDa (Figure 1G)[49]. Interestingly, the effect was
tumor-specific and did not appear on normal cells. EF-induced transient
increase in plasma membrane permeability, with contributions from
structural rearrangement of lipids and protein changes, causing fatigue
of the membrane structure[48]. Since the membrane composition of
cancer cells is altered and more deformable than normal cells that may
help in explaining the inconsistent response to alternating EF[48].
The cell membrane permeability of tumor cells increases in response to
TTFields, allowing transmembrane transport of chemical agents that
explaining the increased efficacy of other drugs to some extent. The
cell-membrane permeabilization also contributes to the release of innate
tumor antigens and activates the immune system[50].
Ion channels in cell membrane can be affected by alternating EF, and the
L-type Ca2+ channels CACNA1C (Cav1.2) were identified
as TTFields target recently[51], thereby influencing cell cycle
progression, cell migration, and clonogenic survival of GBM
cells[52]. Cell membrane potential is a key factor controlling the
switching on and off of ion channels in cell membranes, and has been
identified as a target for TTFields. Using the Schwan equation, it was
found that in tumor cells, TTFields-induced changes in cell membrane
potential can be much higher than 10% of the resting cell membrane
potential, thus affecting intracellular ion homeostasis[53].
TTFields were also reported to disrupt tight junction proteins (e.g.,
claudin 5 and ZO-1) of the BBB to increase the permeability of brain
(Figure 1H)[54]. Till now, the presence of BBB has posed limitations
for the treatment of brain malignancies and the cerebral application of
some agents. TTField-induced opening of BBB is similarly reversible and
expands the range of intracranial drug application.
FACTORS AFFECTING THE EFFICACY OF TTFIELDS
The efficacy of TTFields depends on the specific parameters. For
different types and sites of tumors, different modalities are set to
obtain optimal efficacy. The optimal intensity of EF is different for
different cancer cells. Mouse melanoma cells and rat glioma cells
completely stop proliferating at 1.35 V/cm and 2.25 V/cm
respectively[7], while human non-small cell lung cancer and breast
cancer cells require higher[21]. The frequency range for anti-tumor
effects in most cancers is 100 to 200 kHz[55, 56] (e.g., 200kHz for
human GBM clinically, 120kHz for melanoma cells[7]). In vitro
studies have shown that different GBM cell lines have different optimal
electrical frequencies, 200 kHz for KNS42 and GIN-31, 400 kHz for SF18,
and 100 kHz for U87[57, 58]. The optimal frequency of alternating EF
is inversely proportional to the size of cancer cell[7].
Additionally, the inhibitory effect of tumor proliferation by TTFields
is time-dependent[22, 59], and the effect of EF is strongest when
the direction of EF is parallel to the axis of cell division. Given the
polarity of tumor cells during the division cycle is irregular, applying
EF in different directions is an effective way to increase the efficacy
of treatment for patients[7]. Sequential application of multiple EF
directions every 0.25~1.00s can make the splitting axis
of more cells parallel to the direction of EF[21].
CLINICAL STUDIES OF TTFIELDS IN MALIGNANT BRAIN TUMORS
Along with a deeper understanding of the mechanism of action of
TTFields, translational studies accompanying clinical trials are crucial
for TTFields and are being vigorously pursued. The results of published
clinical scientific researches TTFields therapy in brain malignancies,
have been summarized in Table I. The ongoing clinical trials to further
evaluate the safety and efficacy of TTFields-based combination therapy
have been listed in Table II.
Recurrence glioblastoma
(rGBM)
Defined as a grade IV glioma, GBM has a high recurrence rate. There is
no consensus for the optimal treatment of rGBM, and the only
FDA-approved agent is bevacizumab (a targeted VEGF antibody)[60,
61]. GBM diffusely infiltrates the brain and rarely metastasizes
extracranially, thus is amenable to TTFields therapy[62]. The pilot
trial of TTFields therapy was on 10 patients with rGBM, and median time
to disease progression was 26.1 weeks and mean overall survival (OS) was
62.2weeks, higher than the reported medians of historical control
patients[21]. In the randomized phase III clinical trial (EF-11,
NCT00379470), 237 patients with rGBM were enrolled into two arms:
TTFields versus best physician’s choice chemotherapy (BPC), include
bevacizumab, irinotecan, nitrosurea, carboplatin and TMZ. The results
showed that OS and progression-free survival (PFS) of patients in two
arms were similar (6.6 vs 6.0months, 2.2 vs 2.1months, respectively;
p>0.05)[8]. Although no improvement
was observed in the EF-11 trial, the better quality of life (QoL) and
lighter toxicity favoured the TTFields when compared with chemotherapy
as an option in maintenance phase. Of note, most of the recruited
patients were in advanced stages of the disease (failure of more than 2
chemotherapy agents), and there was heterogeneity in the patients
population. In the OptimalTTF-1 trial (NCT02893137), the combination of
cranial remodeling surgery with TTFields and BPC in patients with rGBM
yielded an OS of 15.5 months and PFS of 4.6 months[63], much higher
than that of TTFields arm in EF-11, and was well tolerated by
patients[8]. The removal of standard craniotomy bone flap increased
the EF intensity at the tumor site and was more effective with multiple
smaller burr holes than with a single craniectomy[63]. Since the new
multimodal approach has showed a preliminary survival benefit,
a large-scale randomized, controlled trials, phase 2 trial
(OptimalTTF-2, NCT0422399) was initialed 2 years ago to valid the novel
combination therapy[64].
New diagnosed glioblastoma (ndGBM)
The standard of care (SOC) for ndGBM is maximal surgical resection, 6
weeks of postoperative RT and temozolomide (TMZ), and 6 months of TMZ
maintenance therapy[65]. In a phase III trial of ndGBM (EF-14,
NCT00916409), 695 patients after completion of chemoradiotherapy were
enrolled into two arms randomly. Compared with standard TMZ maintenance
therapy alone, adding TTFields to standard TMZ maintenance therapy
dramatically improved OS (19.6 vs 16.6 months, respectively;
p < 0.001) and PFS (7.1 vs 4.0 months, respectively;
p < 0.001) of patients[9]. Excitingly enough, the DNA
repair protein O6-methyl-guanine DNA methyltransferase
(MGMT), which has previously been reported to affect the efficacy of
TMZ, did not affect TTFields[38]. EF-14 is the landmark trial of
TTFields therapy, and the NOA-09/CeTeG trial published recently have
verified the feasibility of combination of lomustine and TMZ[66].
Therefore, the combination of TTFields, lomustine and TMZ during
maintenance phase was tested, and the observed PFS was 20 months in 16
patients with MGMT promoter methylated ndGBM that might suggested the
potential benefit of the triple maintenance therapy[66].
TTFields are a promising candidate radiosensitizer, as it induced an
abnormal increase in mitotic catastrophe and DNA damage of
cells[25]. A prospective, single-arm study that recruited 10
patients with ndGBM was conducted to assess the feasibility and safety
of combined RT and TTFields therapy with maintenance TMZ and TTFields.
The mean PFS of this trial was 8.9 months and limited toxicity
reported[67]. When TTFields were given concurrently with RT which
was delivered through the TTFields arrays and with maintenance TMZ, the
improvement in PFS of 9.3 months was illustrated[68]. It follows
that the feasibility of TTFields both as maintenance therapy and
alongside chemoradiotherapy is endorsed by prior clinical practice, and
more large-scale clinical trial, EF-32(NCT04471844), is underway.
Other gliomas
Mesenchymal astrocytoma (MA) is a WHO grade III glioma, and the
experience with the application of TTFields to MA is limited. A
published clinical case for the first time reported that TTFields-based
combination therapy delayed pathological up-gradation from anaplastic
astrocytoma to GBM and prolonged PFS to nearly 10 months[69]. This
case indicated the potential beneficial of TTFields-based therapy in MA,
and ongoing trials of TTFields in a larger cohort of patients with MA
are needed to be evaluated.
Ganglioglioma is classified as grade I, although grow slowly, some
patients will experience recurrence or malignant progression.
Transformation of ganglioglioma to high-grade glioma is rare but usually
with poor prognosis[70]. A patient with a BRAF V600E mutation in a
high-grade glioma originating from ganglioneuroma was treated with
dabrafenib (a selective inhibitor of BRAF V600E) and TTFields after the
failure of TMZ-based therapy. More than 2 years of follow-up have shown
complete response to the combination therapy[71], arguing that
gene-targeted treatment in combination with TTFields therapy may provide
great clinical benefit for glioma with rare variants.
Metastatic tumors
The majority of brain metastases result from lung cancer[72]. The
development of brain metastases complicates many solid tumors, and
attribute to the death of patients with advanced cancer[73]. A METIS
trial enrolling non-small cells lung cancer (NSCLC) patients with 1-10
brain metastases (NCT02831959) who receive stereotactic radiosurgery
(SRS) followed by TTFields (150 kHz, ≥18 hours/day) or supportive care
within 7 days of SRS reported no safety issues in 2018 and is ongoing
currently[74].
PRECLINICAL STUDIES OF TTFIELDS IN MALIGNANT BRAIN TUMORS
With optimal output pattern, TTFields could significantly inhibited the
viability, proliferation, and invasiveness of different cell lines,
irrespective of their genetic
traits[75]. Several studies have shown synergistic effects of
TTFields and targeted agents, of which bevacizumab is widely
applied[76, 77]. Sorafenib is a multi-kinase inhibitor and a
first-line agent for the treatment of high-grade gliomas as well, but it
has failed to improve outcomes when combined with TMZ[78]. While
combining with TTFields, sorafenib significantly inhibited motility,
invasiveness, and angiogenesis of GBM cells[79].
Evolutionary conserved protein
kinase monopolar spindle 1 (MPS1) inhibition, affecting mitotic
processes similarly, when combined with TTFields to GBM cells caused
more than just additive effects. The anti-proliferative benefit of the
combination therapy begins to work earlier than that of the
mono-therapy[80]. Some inhibitors of MPS1 have been developed and
can potentially serve as a bridge for TTFields therapy interruption.
Likewise, hyperthermia has been reported to increase the efficacy of
other approaches against cancers. Combining heat therapy with TTFields
has been reported to enhance each other’s therapeutic effects and
inhibit the metastasis of GBM cells[81]. The combination of these
two physical therapy may be easily tolerated by patients. Since
Ca2+ channels contributes to cellular stress response
to TTFields, combining TTFields with Ca2+ antagonists
(e.g., benidipine) may augment the efficacy and outcome of
TTFields[51]. It provides the possibility of combining TTFields with
Ca2+ antagonists which are already applied in
clinical. In brief, TTFields hold great promise to address the challenge
across the spectrum of the management of patients with high-grade
gliomas by optimizing other treatment strategies.
Given the special immune environment of intracranial tumors, brain
malignancies suppress immune cells activity and anti-cancer function,
and revitalizing central immune system has become the emerging for
malignant brain tumors and experienced tremendous growth[2].
Considering the transformation of tumors under TTFields exposure to a
state more favorable for anti-tumor immune response[47], and its
role of switching on the BBB, TTFields may potentially enhance the
central anti-tumor immune response[54, 82]. At present,
immunotherapeutic approaches for GBM contain: vaccines, checkpoint
inhibitors, CAR-T cells, and oncolytic viruses[2]. Combining
TTFields and anti-PD-1 (programmed cell death protein 1) therapy has
already been proven validity in the resistance to extra-cranial tumors
than single therapy by triggering immune response[44]. Several
clinical trials (e.g., NCT03223103, NCT03405792) to test the
immunogenicity and safety of immunotherapeutic approaches in combination
with TTFields in patients with malignant brain tumors are conducted
currently, which will be valuable to establish a combination of
therapeutic strategies and to elucidate the mechanism of TTFields on the
immune gmicro-environment of malignant brain tumors.
THERAPEUTIC EVALUATION OF TTFIELDS THERAPY
Magnetic resonance imaging (MRI) is the common method for diagnostics
and follow-up of malignant brain diseases, especially the change of MRI
contrast enhancement, which is often considered an indicator of
treatment response or tumor progression[83]. But conventional MRI
cannot assess treatment response reliably due to lack of
specificity[84], and the enhancement can be caused by other
non-tumor-associated processes[85]. Physiological imaging
techniques, including diffusion tensor imaging (DTI), dynamic
susceptibility contrast-perfusion weighted imaging (DSC-PWI) and proton
MR spectroscopy, have great potential in assessing treatment response to
different therapies in patients with GBM. A case reported the experience
in evaluating treatment response to TTFields in combination with TMZ in
a female ndGBM patient using DTI, DSC-PWI and 3D-echo-planar
spectroscopic imaging. Compared with baseline, increased mean
diffusivity and decreased fractional anisotropy, maximum relative
cerebral blood volume, and reduced choline/creatine were noted at 2
months follow-up periods[86]. The results verified the synergistic
effect of TTFields and TMZ chemotherapy can inhibit the growth of tumor.
Positron emission tomography (PET) scanning provides more biological
information than just anatomical information in a non-invasive
way[87]. As the most widely clinical applied tracer,18F-FDG
(18F-2-fluoro-2-deoxy-D-glucose) can be highly taken
up by normal brain tissue, thus limiting the application in patients
with malignant brain tumor[88]. The Response Assessment in
Neuro-Oncology group have recommended more wide-scale diagnostic access
to amino acids-based PET for the management of patients with malignant
brain tumors[89], due to the low uptake by normal brain
tissue[90]. When applied FET
(O-(2-18F-fluoroethyl)-L-tyrosine) PET scanning in
patients with high-grade glioma whose treatment included TTFields, the
data showed increased tumor volume with increased uptake or metabolic
activity and demonstrated with histologically or clinically follow-up
confirmed disease progression. Compared to MRI images, FET PET images
present clearer lesion boundaries (Figure 2)[91]. AMT
(alpha[C-11]-methyl-L-tryptophan) PET scanning has been proven to
detect an early metabolic response in rGBM patients before and after
TTFields. The images indicated that AMT PET can detect the metabolic
alterations of amino acids in GBM cells induced by TTFields earlier than
MRI, therefore helps in clinical decision making, especially in cases
where MRI images are inconclusive[92]. 18F-DASA-23
(1-((2-fluoro-6-18F-fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine)
was introduced to provide the information of the level of pyruvate
kinase M2 (PKM2)[93], which is preferentially expressed in cancer
cells and contributes to anabolic glucose metabolism[94]. A research
project working on manipulation of 18F-DASA-23
radiotracer to detect the impairment of GBM glycolytic metabolism
through down-regulation on the expression of PKM2 by TTFields was
published[95]. This research first proved that TTFields can cause a
shift in GBM metabolism from glycolysis to oxidative phosphorylation.
Even in the presence of sufficient oxygen, cancer cells prefer to use
the inefficient process of glycolysis for energy production[96], the
so-called warburg effect, which
produces lactic acid that is beneficial for tumor growth and
metastasis[97]. Warburg effect attribute to the tumor progression
and provide suitable and appropriate atmosphere for tumor to
metastasize. Therefore, the metabolic reprogramming of tumor cells by
TTFields may also be one of its significant anti-cancer mechanisms.
TTFIELDS IMPROVE THE
QUALITY OF PATIENT’S LIFE
Till now, accumulating clinical experience have confirmed the safety of
TTFields therapy, and no significantly life-threatening TTFields-related
event has been reported[8, 9]. The most frequent TTFields-related
side effect is skin reaction[98], while other therapies often cause
serious systematic side effects. The array-associated skin toxicity
including rash, irritation, erythema, pruritus, contact dermatitis,
ulceration, infection and skin breakdown, that could be cured with
topical corticosteroid creams, topical and oral antibiotics, and
isolation the affected skin surface from adhesives or pressure[99].
In brief, TTFields are linked to prolonged survival outcomes, minimal
adverse effects and easily manageable.
According to the patient registration dataset, the clinical efficacy of
TTFields on patients was significantly improved with ≥75% daily
adherence (≥18 hours/day) compared with <75%[100]. In
other words, the efficacy of TTFields on patients with brain
malignancies critically depends on their high compliance rate, and
patients must abide by a long daily regimen of continuous TTFields for
at least 4 weeks that might bring inconvenience for patients. To improve
the ease of use, home medical devices were developed, allowing patients
to receive treatment by simply wearing the devices on their heads and
not interfering with their daily activities. The most commonly employed
TTFields delivery system consists of four transducer arrays, a field
generator, and a power resource. The distribution of the arrays can be
determined by the NovoTAL software to ensure that the best field
strength is obtained at the tumor site[13]. EF is delivered through
the transducer arrays attached to the skin, and patients with lesions in
the brain need to make an adequate commitment to daily skin care,
regular hair shaving, and carrying sufficient power sources during
TTFields therapy. Fortunately, according to the analysis of EF-14 trial,
adding TTFields to cancer treatment does not worsen patient function and
well-being production , such as role, social, and physical
functioning[98]. Patients can
enjoy symptomatically stability during TTFields therapy, meanwhile,
their quality of life can be maintained.
Since late 2019, the COVID-19 epidemic has forced a change in the
treatment paradigm brought about by quarantine limitations, that might
become the barrier to the routine treatment of patients with cancer.
TTFields can be administered via telemedicine and confer a competitive
advantage to be conveniently employed for the management of GBM patients
during the COVID-19 pandemic[101]. Furthermore, reducing patient
visits to health care facilities and cutting down on potential exposure
to virus will ensure the safety of ongoing treatment.
CONCLUSION
As a noninvasive physical therapy, TTFields have exhibited unique
advantages in the treatment of patients with malignant brain tumors and
are well suited for clinical trials exploring combined approaches to the
management of patients due to the minor adverse effects and absence of
toxicity. Nevertheless, the application of TTFields in pediatric
high-grade glioma is relatively rare, with few case reports regarding
safety analysis, and needs to be corroborated in a larger patient
cohort[102]. TTFields do not have a half-life and enable sustainable
treatment[103], which can be applied between chemoradiotherapy or
concurrently with RT[104]. Furthermore, TTFields are inherently
non-specific to tumor types, may cause therapeutic effects for a wide
range of solid tumors, and are being investigated for application to
extra cranial tumors[44, 56, 105]. Unfortunately, the mechanism of
TTFields is far less clear and suffers from skepticism than other
therapies[106]. Pharmacological profiling may be helpful in
revealing the synergistic effects of TTFields in combination with other
therapeutic agents. Continued enhancement of research and understanding
of the molecular mechanisms will facilitate the adoption of this novel
therapy for integration into existing or new treatment strategies.
Although already an established treatment for newly diagnosed or
recurrent GBM in adults by FDA and have been proven effective in
combination with SOC of GBM, TTFields were not added to SOC by the
leading experts[104]. High cost is the biggest obstacle to
broadening the application of TTFields, which needs to be addressed
immediately, and cost-effectiveness studies are recommended[107,
108]. To improve the convenience of use, further refinement of the
TTFields system is required to improve the ease of use and device
performance through physical and other means (e.g., changing the size
and weight of the instrument, the implanting of electrodes around the
tumor). Conducting an outpatient clinic for TTFields therapy
consultation is suggested, which may lead to a great promotion of
motivation and compliance rate, and ensures the clinical efficacy of
TTFields[109]. Besides, it’s still a mission for researchers to
figure out the biomarkers to select the suitable patients who might be
responsive to TTFields, and the markers or technique predicting optimal
frequency or response in different cancer types or individuals. The
framework of TTFields therapy, from patient selection and treatment to
follow-up efficacy assessment system, needs to be refined in detail. As
a innovative treatment with great potential for tumor therapy, we firmly
believe that TTFields treatment system will be a boon to patients with
cancer.